Chloromethylation of aromatic substrates and polymers is carried out readily using chloromethylether (CME) or bis-chloromethyl ether (BCME) (G. A. Olah, Friedel-Crafts and related reaction, Vol.II, Part 2, p. 659, J. Wiley & Sons, N.Y. 1964). Since both reagents have been listed as highly carcinogenic, the alternative use of formaldehyde or paraformaldehyde in acidic aqueous solutions has been tried [R. Hauptmann and G. Schwachula, Z. Chem., 8, 227-8 (1968)]. This method was found ineffective in the case of hydrophobic polymeric materials and also unsafe, since BCME is formed under those condtions, and acts as the active chloromethylating intermediate. The same holds true for other methods using formaldehyde derivatives, as the methylalchlorosulfonic acid method.
The major hazard in the use of CME and BCME lies in their high volatility which causes lung cancer: S. Laskin, M. Kuschner, R. T. Drew, V. P. Cappiello and N. Nelson Arch Enviromen. Health, Vol 23, 135 (1971) and L. D. Taylor and N. s. Simon, J. of Physical Chemistry, Vol. 78, 2696 (1974). There exists clear evidence that reactions of formaldehyde and chloride ions lead to BCME. [J. C. Tou and G. T. Kallos, J. Analytical Chemistry, Vol. 48, 958 (1976)] and that formaldehyde causes induction of nasal cancer in the rat [R. T. Albert, A. R. Sellakumar, S. Laskin, M. Kuschner, N. Nelson and C. A. Snyder, JNCl, Vol 68, 589 (1982)]. Because of the high volatility of CME and BCME, OSHA has issued stringent air control regulations [Occupational Safety and Health Standards Part III, Department of Labor, Occupational Safety and Health Administration, Fed Regist 39 (Tuesday, Jan 29), 3576-3797 (1971)]of those carcinogens.
We have now discovered, that long chain alkyl-halomethyl ethers are very effective and safe halomethylating agents, since they offer the following advantages:
1. The reagents are readily prepared in quantitative yields, and easily stored.
2. The reagents are powerful halomethylating agents and stable to various reaction conditions.
3. The reagents have low volatility. Increasing the size of the R group or selecting R as a small polymer residue, e.g., a polyvinyl-alchol group, yields reagents of extremely low volatility.
4. The alcohol can be recovered after the chloromethylation and reused.
5. Control over the reaction parameters avoids formation of side products such as CME or BCME.
6. The hydrophobic alcohols do not deactivate the Friedel-Crafts catalyst and may be applied in considerable excess.
In comparison, the compounds suggested by Olah et al. [(G. A. Olah, D. A. Beal, S. H. Yu and J. Olah, Synthesis 560-561 (1974)][G. A. Olah, D. A. Beal, and J. A. Olah, J. Org. Chem., 41 1627-1631 (1976)] possess high volatilities; after "torr)," and boiling points range between 70.degree.-94.degree. C. at 5 torr), incorporate bis-halo-methyl groups which are an order of magnitude more hazardous than the mono-halomethyl compounds. Furthermore, compounds of type 1 are not economical, since only one of the CH.sub.2 X groups is used, the other group being lost as CH.sub.2 O moiety.
In addition, reagents with the bis-halomethyl group are much more hazardous than the corresponding mono-halomethyl compounds as indicated by Van Duuren, Goldschmidt and Seidman [Cancer Research Vol 35, 2553 91975)] for bis-1.4-chloromethoxybutane and related compounds. In addition, the side product, tetrahydrofuran cannot be converted to 1 and reused.
The purpose of this invention is to provide halomethylating agents of improved safety, where emphasis is on improved safety in the preparation of the reagents, and in their use in halomethylation reactions, For that purpose careful attention is given not only to the identity of the reagent but to its preparation, with suitable control of reaction conditions and reactant ratio to avoid presence of any free CH.sub.2 O which would lead to BCME. In addition to synthetic procedures we disclose also levels of BCME as found in combined gas chromatographic mass spectral analysis and consequently specify methods and conditions for safe preparation and handling of halomethylating reagents. The long-chain alkyl-halomethylethers are prepared by reacting a suitable alcohol with formaldehyde or paraformaldehyde in an organic solvent to give the desired product. The reaction can be carried out at ambient temperature and pressure and gives a high yield and a product of high purity. When the product is used as halomethylating agent, the alcohol is set free and can be used for the preparation of further batches of halomethylating agents.
Tin-tetrachloride and titanium tetrachloride were used as the Friedel-Crafts Lewis acid catalysts. However, other catalysts known to be effective in chloromethylation (G. A. Olah, Friedel-Crafts and related reactions, Vol. II, Part 2, p. 659, J. Wiley & Sons, N.Y. 1964) can be used, depending on the specific activity required, the need to avoid further cross-linking reaction, or pertinent price considerations. The reactivity of the halomethylating agents was established by reactions with simple aromatic substrates, such as benzene and alkylbenzene derivatives, and also on styrene-divinylbenzene copolymers. The alkylchloromethylether compounds can be reacted with various styrene-divinylbenzene copolymers in common swelling solvents applied in chloromethylation, e.g. halogenated paraffins, or in other solvents such as alkanes. Common Lewis-acid catalysts, such as stannic chloride, zinc chloride, or aluminium chloride are used. The most preferred conditions are chloromethylation in CH.sub.2 Cl.sub.2 or CHCl.sub.3 at room temperature. The ratio of alkylchloromethyl ether-to-polymer-to-SnCl.sub.4 varies according to the reactivity of the polymer, which is determined by the swelling properties of the polymer. After the reaction, the polymer is filtered off, washed with chloroform, then with methanol and reacted with an amine to yield an anion exchange resin. The solution is washed with aqueous HCl solution to remove the catalyst, then with water, and the ROH product is recovered directly or after purification by distillation or dialysis. As an alternative route, "one pot preparation" of anion exchange resins from the non-functionalized copolymers is possible. The halomethylating agent is first prepared, and the copolymer and Lewis acid catalyst is then added, followed, after halomethylation by the amine. The final product, an anion exchange resin, is obtained, and any excess of the halomethylalkylether is destroyed, but the starting alkanol is regenerated. Thus, the workup of the "one pot reaction" does not involve handling of any alkylating agent.
The selection of ROCH.sub.2 X reagent is governed by the first five considerations outlined earlier. In addition ROH should be inexpensive and commercially available. Thus alkanols with R, being shorter than a four carbon chain or longer than twenty carbon chains, are excluded. Alkanols in the ranges of 6-12 carbon atoms are practically possible but the need to avoid the presence of even a small amount of CME or BCME (criterion 5, above), dictates that not only the properties of the final reagents, but also how they effect the presence of undesired BCME must be considered. In other words, the relative rates of formation of ROCH.sub.2 Cl against the rate of formation of ClCH.sub.2 OCH.sub.2 Cl must be one of the major criteria of selecting the best ROCH.sub.2 Cl reagent. The following examples illustrate the synthesis of long chain halomethylalkyl ether from various classes of alcohols: primary, secondary, benzylic, tertiary, phenolic, and polyols.